One major goal of neuroscience is to unravel the neural circuitry and processing that control animal behaviors. A greater understanding of these systems can help in the treatment of diseases which are currently alleviated using invasive deep brain stimulation. Hence, methods for non-invasive, remote control of neuronal activity are at the top of the wish list for many neuroscientists. The goal is to develop a method to stimulate specific subsets of neurons deep in the brain without requiring a physical connection to the outside world. The objective of this proposal is to demonstrate that alternating magnetic fields may be used to stimulate neurons deep inside mammalian brains by using nanoparticles to convert the magnetic field energy into localized heat and genetically expressing a temperature sensitive ion-channel which then converts the heat stimulus into membrane depolarization. Magnetic fields interact only weakly with tissue, making them well suited for deep tissue stimulation. The fields and frequencies used will be comparable to those used in standard MRI machines. The approach contains several extremely innovative and novel concepts: (1) magnetic neuro- stimulation, (2) conversion of magnetic fields into heat to create a local and biologically detectable stimulus, (3) targeting nanoparticles to the cell membrane to achieve sub-cellular localization of the heating, and (4) genetic engineering of neurons to synthesize magnetic nanoparticles are all novel and innovative ideas. The proposed research is highly significant because it provides a method by which the relationship of neuronal circuits to animal behavior can be studied. This capability will (i) increase our understanding of normal and pathological brain function, and (ii) provide new therapeutic avenues for remote stimulations in conditions with reduced natural stimulations, such as traumatic brain injuries, Parkinson's disease, dystonia or major depression. PUBLIC HEALTH RELEVANCE: The proposed EUREKA research is relevant to public health because a remote neuro- stimulation method will allow neuroscientists to gather the knowledge of how specific neuronal circuitry governs animal and human behavior. The results of the proposed research are expected to lead to improved treatments of ailments benefiting of specific stimulation of specific neurons or group of neurons, such as traumatic brain injuries, Parkinson's disease, and dystonia or major depression, as well as peripheral paralysis. Thus the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to protect and improve mental health.